Opioid receptor antagonists

ABSTRACT

A compound of the formula I: (I) wherein the variables are as described herein, or a pharmaceutically acceptable salt, solvate, enantiomer, racemate, diastereomer or mixture thereof, formulations and methods of use thereof are disclosed.

The present invention is in the field of medicinal chemistry. Theinvention relates specifically to compounds useful as opioidantagonists, methods of treatment, methods of using, and pharmaceuticalcompositions thereof.

BACKGROUND

Three types of opioid receptors, mu, kappa, and delta opioid receptorsare generally reported. Recent evidence points to the interactionsbetween receptor dimer combinations of mu, kappa and/or delta receptors(called heterodimers) as also contributing to opioid activity. Opioidreceptors and their normal regulation or lack thereof, has beenimplicated in disease states including irritable bowel syndrome, nausea,vomiting, pruritic dermatoses, depression, smoking and alcoholaddiction, sexual dysfunction, stroke and trauma in animals. Thereforeit is not surprising that the ability to antagonistically bind opioidreceptors has been shown to produce ameliorative, preventative and/ortreatment effects in animals including humans afflicted with one or moreof these disease states.

More recently, antagonists of the opioid receptors have been found toincrease metabolic energy consumption, and reduction of weight in obeserats while maintaining muscle mass. These findings indicate that aneffective opioid antagonist may be useful in preventing, treating and/orameliorating the effect of obesity. Considering the percentage of thepopulation that is obese in Western societies and the indirect costsassociated with treating the effects and symptoms of obesity and RelatedDiseases, the importance of these findings cannot be overstated.

Though many opioid antagonists have been disclosed, the search continuesfor alternative and/or improved or more effective antagonists having anoverall benefit to the patient with little or no major side effects.U.S. Pat. No. 4,891,379 disclosed and claimed phenylpiperidine opioidantagonists useful for the treatment of diabetes and obesity. Inparticular, U.S. Pat. No. 4,891,379 disclosed the compound LY 255582represented by the structure

U.S. Pat. No. 4,191,771 also disclosed and claimed compounds useful asopioid antagonists. Also, bicyclic analogs of phenyl piperidine havebeen prepared and reported as opioid antagonists in Wentland, et al.,Biorganic and Medicinal Chemistry Letters 11 (2001) 623-626; see alsoWentland, et al., Bioorganic and Medicinal Chemistry Letters 11 (2001)1717-1721. Finally, European Patent application number EP 1 072592A2filed May 18, 2000, discloses phenylpiperidine compounds of formula I

wherein A, D, R¹, R², R³ X, and n have meanings given in thedescription, which are useful in the prophylaxis and in the treatment ofdiseases mediated by opioid receptors such as pruritus.

Regardless of these and other disclosures of compounds useful as opioidreceptor antagonists, there remains an unmet medical need for a safe,effective and/or alternate treatment or prophylaxis of diseasesassociated with opioid receptors, particularly obesity and RelatedDiseases.

SUMMARY OF THE INVENTION

The present invention provides a compound of the formula (I)

wherein

-   when K is 0, one of X₁, X₂, X₃, X₄, is a S or O atom and the others    are independently selected from C, CH, or N; and wherein when j is    0, one of X₅, X₆, X₇, and X₈ is S, or O, and the others are    independently selected from C, CH, or N; provided that both k and j    are not simultaneously equal to zero or 1; and provided that each of    rings A or B has no more than 2 nitrogen atoms; and provided that    double bonds in the rings are present or absent as needed to    maintain appropriate valency;-   n is 0, 1, 2, or 3;-   k is 0 or 1; j is 0 or 1;-   p is 0, 1 or 2;-   E is O or NH;-   R¹ and R² are independently selected from hydrogen, C₁-C₈ alkyl,    C₂-C₈ alkenyl, C₂-C₈ alkynyl, phenyl, C₁-C₁₀ alkylaryl, C(O)C₁-C₈    alkyl, CO(O)C₁-C₈alkyl, SO₂C₁-C₈ alkyl, SO₂C₁-C₁₀ alkylaryl, or    SO₂C₁-C₈ alkylheterocyclic, C₄-C₁₀ alkylcycloalkane, C₁-C₈    alkoxyalkyl, (CH₂)_(n)C(O)OR⁸, (CH₂)_(n)C(O)R⁸, (CH₂)_(m)C(O)NR⁸R⁸,    and (CH₂)_(m)NSO₂R⁸; wherein each of the alkyl, alkenyl, and aryl    groups are optionally substituted with one to five groups    independently selected from C₁-C₈ alkyl, C₂-C₈ alkenyl, phenyl,    C₁-C₈ alkylaryl, C(O)C₁-C₈ alkyl, CO(O)C₁-C₈ alkyl C₁-C₈ alkoxy,    SO₂C₁-C₈ alkyl, SO₂C₁-C₈ alkylaryl, SO₂C₁-C₈ alkylheterocyclic,    C₄-C₁₀ alkylcycloalkane, (CH₂)_(n)C(O)OR⁸, (CH₂)_(n)C(O)R⁸; and    wherein R¹ and R² may optionally combine with each other to form a    4, 5, 6, or 7-member nitrogen-containing heterocycle which    nitrogen-containing heterocycle may have substituents selected from    the group consisting of oxo, amino, C₁-C₈ alkyl, C₂-C₈ alkenyl,    C₂-C₈ alkynyl, phenyl, C₁-C₈ alkylaryl, C(O)C₁-C₈ alkyl, CO(O)C₁-C₈    alkyl, halo, C₁-C₈ haloalkyl;-   R³ and R^(3′) are each independently selected from Hydrogen, C₁-C₈    alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₁-C₈ alkoxy, C₁-C₈ thioalkyl,    phenyl, aryl, C₁-C₈ alkylaryl;-   R⁴ and R⁵ are each independently selected from Hydrogen, C₁-C₈    alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₁-C₈ alkoxy, halo, C₁-C₈    haloalkyl, phenyl, aryl, C₁-C₈ alkylaryl, (CH₂)_(m)NSO₂C₁-C₈ alkyl,    (CH₂)_(m)NSO₂phenyl, (CH₂)_(m)NSO₂aryl, —C(O)C₁-C₈ alkyl, or    —C(O)OC₁-C₈ alkyl; wherein each R⁴ or R⁵ is attached to its    respective ring only at carbon atoms, and wherein y is 0, 1, 2, or    3; and wherein z is 0, 1, 2, or 3;-   R⁶ and R⁷ are each independently selected from hydrogen, C₁-C₈    alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C(O)C₁-C₈ alkyl, hydroxy, C₁-C₈    alkoxy, SO₂C₁-C₈ alkyl, SO₂C₁-C₈ alkylaryl, or SO₂C₁-C₈    alkylheterocyclic, aryl, C₁-C₈ alkylaryl, C₃-C₇ cycloalkane, C₁-C₁₀    alkylcycloalkane, (CH₂)_(n)C(O)OR⁸, (CH₂)_(n)C(O)R⁸,    (CH₂)_(m)C(O)NR⁸R⁸, and (CH₂)_(m)NSO₂R⁸; wherein each of the alkyl,    alkenyl, and aryl groups are optionally substituted with one to five    groups independently selected from C₁-C₈ alkyl, C₂-C₈ alkenyl,    phenyl, and C₁-C₈ alkylaryl; and wherein R⁶ and R⁷ may independently    combine together, and with the nitrogen atom to which they are    attached or with 0, 1, or 2 atoms adjacent to the nitrogen atom to    which they are attached to form a 4, 5, 6, or 7-membered nitrogen    containing heterocycle which nitrogen containing heterocycle may    further have substituents selected from the group consisting of oxo,    amino, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, phenyl, C₁-C₈    alkylaryl, C(O)C₁-C₈ alkyl, CO(O)C₁-C₈ alkyl, hydroxy, C₁-C₈ alkoxy,    halo, and haloalkyl;-   R⁸ is hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₅-C₈ alkylaryl,    —C(O)C₁-C₈ alkyl, or —C(O)OC₁-C₈ alkyl; m is 1, 2, or 3; or a    pharmaceutically acceptable salt, solvate, enantiomer, racemate,    diastereomers or mixtures thereof.

The present invention also provides a method for the prevention,treatment and/or amelioration of the symptoms of obesity and RelatedDiseases comprising administering a therapeutically effective amount ofa compound of formula I to a patient in need thereof.

The present invention also provides a pharmaceutical formulationcomprising a compound of formula I in association with a carrier,diluent and/or excipient.

The present invention also relates to a method for the treatment and/orprophylaxis of obesity and Related Diseases including eating disorders(bulimia, anorexia nervosa, etc.), diabetes, diabetic complications,diabetic retinopathy, sexual/reproductive disorders, depression,anxiety, epileptic seizure, hypertension, cerebral hemorrhage,congestive heart failure, sleeping disorders, atherosclerosis,rheumatoid arthritis, stroke, hyperlipidemia, hypertriglycemia,hyperglycemia, hyperlipoproteinemia, substance abuse, drug overdose,compulsive behavior disorders (such as paw licking in dog), andaddictive behaviors such as for example, gambling, and alcoholism,comprising administering a therapeutically effective amount of acompound of formula I or a pharmaceutically acceptable salt, solvate,enantiomer, racemate, diastereomer or mixture thereof.

The present invention provides a compound of formula (I) useful for themanufacture of a medicament for the treatment, prevention and/oramelioration of symptoms associated with obesity and Related Diseases.

In another embodiment, the present invention provides a compound offormula I or a pharmaceutically acceptable salt, solvate, enantiomer,racemate, diastereomer or mixture thereof, useful as an appetitesuppressant.

The present invention provides a method of achieving weight loss whilemaintaining or minimizing the loss of lean muscle mass.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term “patient” includes human and non-human animalssuch as companion animals (dogs and cats and the like) and livestockanimals.

The preferred subject of treatment, amelioration and/or prevention ofobesity and Related Diseases is a human.

The terms “treating” and “treat”, as used herein, include theirgenerally accepted meanings, i.e., preventing, prohibiting, restraining,alleviating, ameliorating, slowing, stopping, or reversing theprogression or severity of a pathological condition, of sequela thereof,described herein.

The terms “ameliorating” “preventing”, “prevention of”, “prophylaxis”,“prophylactic” and “prevent” are used herein interchangeably and referto reducing the severity of the symptoms associated with obesity andRelated Diseases in a patient afflicted with same or reducing thelikelihood that the recipient of a compound of formula I will incur ordevelop any of the pathological conditions, or sequela thereof,described herein.

As used herein, the term “effective amount” is synonymous with“effective dose” and means an amount of a compound of formula I that issufficient in one or more administrations for preventing, amelioratingor treating a condition, or detrimental effects thereof, hereindescribed, or an amount of a compound of formula I that is sufficientfor antagonizing the opioid receptors to achieve the objectives of theinvention.

The term “pharmaceutically acceptable” is used herein as an adjectiveand means substantially non-deleterious to the recipient patient.

The term “Active Ingredient” as used herein means a compound of formulaI or a combination of compounds of formula I or a combination of acompound of formula I and a co-antagonist of the opioid receptor.

The term “formulation”, as in pharmaceutical formulation, or“pharmaceutical composition” is intended to encompass a productcomprising the active ingredient (compound of formula I), and the inertingredient(s) that make up the carrier, as well as any product whichresults, directly or indirectly, from combination, complexation oraggregation of any two or more of the ingredients, or from dissociationof one or more of the ingredients, or from other types of reactions orinteractions of one or more of the ingredients. Accordingly, thepharmaceutical formulations of the present invention encompass anyeffective composition made by admixing a compound of the presentinvention and a pharmaceutical carrier. The pharmaceutical formulationsof the present invention also encompass a compound of the formula I anda pharmaceutically acceptable co-antagonist of opioid receptors usefulfor the treatment and/or prevention of obesity or Related Diseases.Accordingly a pharmaceutical formulation of a compound of formula Iincludes a pro-drug formed in-vivo upon administration of a compound offormula I to a patient in need thereof.

The term “co-antagonist” of the opioid re eptor as used herein,represents a compound which is known to be therapeutically effective inthe treatment and/or prevention of obesity

The term “Related Diseases” as used herein refers to such symptoms,diseases or conditions caused by, exacerbated by, induced by or adjunctto the condition of being obese. Such diseases, conditions and/orsymptoms include but are not limited to eating disorders (bulimia,anorexia nervosa, etc.), diabetes, diabetic complications, diabeticretinopathy, sexual/reproductive disorders, depression (particularlythat induced by the awareness and loss of self esteem associated withobesity), anxiety, epileptic seizure, hypertension, cerebral hemorrhage,congestive heart failure, sleeping disorders, atherosclerosis,rheumatoid arthritis, stroke, hyperlipidemia, hypertriglycemia,hyperglycemia, and hyperlipoproteinemia.

The term “suitable solvent” refers to any solvent, or mixture ofsolvents, inert to the ongoing reaction that sufficiently solubilizesthe reactants to afford a medium within which to effect the desiredreaction.

The term “mutual solvent” means a solvent that is used to dissolvesufficiently, two or more components of a reaction or mixture separatelyprior to reaction or mixing, that is a solvent common to more than onereagents or components of a mixture.

The term “nitrogen containing heterocycle” refers to a monocycle whichis a 4, 5, 6, or 7-member ring containing 1, 2 or 3 nitrogen atoms inaddition to the carbon atoms completing the ring size, or a combinationof 1 nitrogen atom and 1, or 2 atoms selected from oxygen, and sulfur inaddition to the appropriate number of carbon atoms completing the ringsize. A nitrogen containing heterocycle as used here may have 0, 1 or 2double bonds.

The term C₁-C₈ alkyl refers to and includes all groups, structuralisomers and/or homologues of alkyl groups having from 1 to 8 carbonatoms. When the term C₁-C₈ alkyl precedes or prefixes another group, theterm C₁-C₈ alkyl, only limits the number of carbon atoms in the alkylcomponent. For example C₁-C₈ alkylaryl, means an aryl group having aC₁-C₈ alkyl group substituent such that the number of carbon atoms inthe group C₁-C₈ alkylaryl is effectively the number of carbon atoms inthe aryl group plus the number of carbon atoms in the C₁-C₈ alkyl group.Similarly, the term C₁-C₈ alkylcycloalkane, refers to a cycloalkanegroup having a C₁-C₈ alkylsubstituent, and wherein the entire groupC₁-C₈ alkylcycloalkane may itself be a substituent attached at eitherthe alkyl group or the cycloalkyl group to a susbtrate.

The term “cycloalkane” means cycloalkanes having from 3 to 8 carbonatoms i.e. from cyclopropane to cyclooctane unless otherwise indicated.Accordingly, the term C₃-C₈ cycloalkane referes to cycloalkanes rangingfrom cyclopropyl to cycloctyl inclusive.

The term “halo” as used herein refers to a halogen including fluorine,chlorine, bromine or iodine.

As used herein the terms “alkenyl” refers to straight or branched carbonatoms having 1 or 2 carbon-carbon double bonds.

As used herein the terms “alkynyl” refers to straight or branched carbonatoms having 1 or 2 carbon-carbon triple bonds.

As used herein the term “alkoxy” refers to the group “O-alkyl” whereinalkyl is as indicated for the specific situation or as definedpreviously.

The term “aryl” as used herein refers to compounds or groups having theHückel 4n+2 pi electron arrangement and includes phenyl benzyl,naphthyl, but excludes carbazoles.

As used herein, the term “protecting group” refers to a group useful formasking reactive sites in a molecule to enhance the reactivity ofanother group or allow reaction at another desired site or sitesfollowing which the protecting group may be removed. Protecting groupsare usually used to protect or mask groups including but not limited to—OH, —NH, and —COOH. Suitable protecting groups are known to one ofskill in the art and are described in Protecting groups in OrganicSynthesis, 3^(rd) edition, Greene, T. W.; Wuts, P. G. M. Eds., JohnWiley and Sons, New York 1999.

As used herein, the term “solvate” is a form of the compound of theinvention wherein a crystal or crystals of a compound of the inventionhave been formed from a stoichiometric or non-stoichiometric amount ofthe compound of formula I and a solvent. Typical solvating solventsinclude for example, water, methanol, ethanol, acetone anddimethylformamide.

In those instances where a compound of the invention possesses acidic orbasic functional groups, various salts may be formed which are morewater soluble and/or more physiologically suitable than the parentcompound. Representative pharmaceutically acceptable salts, include butare not limited to, the alkali and alkaline earth salts such as lithium,sodium, potassium, calcium, magnesium, aluminum and the like. Salts areconveniently prepared from the free acid by treating the acid insolution with a base or by exposing the acid to an ion-exchange resin.

Included within the definition of pharmaceutically acceptable salts arethe relatively non-toxic, inorganic and organic base addition salts ofcompounds of the present invention, for example, ammonium, quaternaryammonium, and amine cations, derived from nitrogenous bases ofsufficient basicity to form salts with the compounds of this invention(see, for example, S. M. Berge, et al., “Pharmaceutical Salts,” J. Phar.Sci., 66: 1-19 (1977)). Moreover, the basic group(s) of the compound ofthe invention may be reacted with suitable organic or inorganic acids toform salts such as acetate, benzenesulfonate, benzoate, bicarbonate,bisulfate, bitartrate, borate, hydrobromide, camsylate, carbonate,clavulanate, citrate, chloride, edetate, edisylate, estolate, esylate,fluoride; fumarate, gluceptate, gluconate, glutamate,glycolylarsanilate, hexylresorcinate, hydrochloride, hydroxynaphthoate,hydroiodide, isothionate, lactate, lactobionate, laurate, malate,malseate, mandelate, mesylate, methylbromide, methylnitrate,methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, palmitate,pantothenate, phosphate, polygalacturonate, salicylate, stearate,subacetate, succinate, tannate, tartrate, tosylate, trifluoroacetate,trifluoromethane sulfonate, and valerate.

A compound of the invention as illustrated by formula I may occur as anyone of its positional isomers, stereochemical isomers or regioisomers,all of which are objects of the invention. Certain compounds of theinvention may possess one or more chiral centers, and thus, may exist inoptically active forms. Likewise, when the compounds contain an alkenylor alkenylene group, there exists the possibility of cis- andtrans-isomeric forms of the compounds. The R- and S-isomers and mixturesthereof, including racemic mixtures as well as mixtures of enantiomersor cis- and trans-isomers, are contemplated by this invention.Additional asymmetric carbon atoms can be present in a substituent groupsuch as an alkyl group. All such isomers as well as the mixtures thereofare intended to be included in the invention. If a particularstereoisomer is desired, it can be prepared by methods known in the artby using stereospecific reactions with starting materials which containthe asymmetric centers and are already resolved or, alternatively bymethods which lead to mixtures of the stereoisomers and subsequentresolution by known methods. For example, a racemic mixture may bereacted with a single enantiomer of some other compound i.e. a chiralresolving agent. This changes the racemic form into a mixture ofstereoisomers and diastereomers, because they have different meltingpoints, different boiling points, and different solubilities and can beseparated by conventional means, such as, for example, crystallizationor chromatography.

The compound(s) of the present invention have shown anorexigeniceffects, and are thus useful as appetite suppressants either as a singletherapy or in conjunction with exercise and/or other effective appetitesuppressing or weight loss medications.

The efficacy of the compounds of the present invention have been shownby their activity in several models including an SPA, and GTP-gamma Sbinding assays, and an opioid receptor ex-vivo binding assay.

PREFERRED EMBODIMENTS OF THE INVENTION

A compound of formula I preferably exists as the free base or apharmaceutically acceptable salt. More preferred is the pharmaceuticallyacceptable salt, wherein the salt is the hydrochloride salt, thebisulfate salt, mesylate or the oxalic acid salt of the compound offormula I.

Preferred embodiments of the compound of formula I include thesubstructures Ia, Ib, and Ic as shown below:

For the groups R¹ and R²

Preferred R¹ and R² groups are independently selected from the groupconsisting of hydrogen, methyl, ethyl, propyl, pentyl, and isopropyl.Also preferred are R¹ and R² groups independently selected from thegroup consisting of hydrogen, methyl, ethyl, propyl, isopropyl, phenyl,

each of which is optionally substituted with a group selected from thegroup consisting of halogen, C₁-C₈ alkyl, C₁-C₈ haloalkyl, C₁-C₈thioalkyl, C₁-C₈ alkylamino, phenyl, C₁-C₈ alkylsubstituted phenyl,C₄-C₈ heterocycle or C₁-C₄ alkyl heterocycle; or combine with a groupselected from C₁-C₈ alkyl, halogen, C₁-C₈ haloalkyl, C₁-C₈ thioalkyl,C₁-C₈ alkylamino, phenyl, C₁-C₈ alkylsubstituted phenyl, C₄-C₈heterocycle or C₁-C₄ alkyl heterocycle to form a substituted orunsubstituted bicycle.

Also preferred are R¹ and R² groups which combine with each other orwith 1 or 2 atoms adjacent to the nitrogen atom to form a group selectedfrom the group consisting of hydrogen, methyl, ethyl, propyl, pentyl,and isopropyl,

each of which is optionally substituted with a group selected from thegroup consisting of halogen, C₁-C₈ alkyl, C₁-C₈ haloalkyl, C₁-C₈thioalkyl, C₁-C₈ alkylamino, phenyl, C₁-C₈ alkylsubstituted phenyl,C₄-C₈ heterocycle or C₁-C₄ alkylheterocycle.Preferred R³ and R^(3′) Groups

A preferred R³ is hydrogen. A preferred R^(3′) group is selected fromhydrogen, methyl, ethyl, propyl, isopropyl, phenyl and benzyl.

Preferred R⁴ Groups

A preferred R⁴ group is selected from the group consisting of hydrogen,halo, C₁-C₅ alkyl, C₁-C₅ haloalkyl, C₁-C₅ alkoxy, C₁-C₅ alkylamino,phenyl, C₁-C₅ alkylphenyl, C1-C5 alkylcycloalkyl, and C₁-C₅ thioalkyl.More preferred is a R⁴ group selected from the group consisting ofhydrogen, methyl, ethyl, isopropyl, bromo, chloro, fluoro,trifluoromethyl, methoxy, ethoxy, thiomethyl, phenyl, and benzyl. A mostpreferred R⁴ group is selected from the group consisting of hydrogen,methyl, ethyl, isopropyl, fluoro, chloro, bromo, trifluoromethyl,methoxy, ethoxy, propoxy, isopropoxy, and benzyl.

Though the groups R⁴ and R⁵ may exist as multiple substituents on theirrespective ring substrates, a preferred embodiment of the inventioninvolves compounds wherein each of R⁴, and R⁵ when present are singly ordoubly substituted on their respective ring substrates.

Preferred R⁵ Groups

A preferred R⁵ group is selected from the group consisting of hydrogen,halo, C₁-C₅ alkyl, C₁-C₅ haloalkyl, C₁-C₅ alkoxy, C₁-C₅ alkylamino,phenyl, C₁-C₅ alkylphenyl, C₁-C₅ alkylcycloalkyl, and C₁-C₅ thioalkyl.More preferred is an R⁵ group selected from the group consisting ofhydrogen, methyl, ethyl, isopropyl, bromo, chloro, fluoro,trifluoromethyl, methoxy, ethoxy, thiomethyl, phenyl, and benzyl. A mostpreferred R⁵ group is selected from the group consisting of hydrogen,methyl, ethyl, isopopropyl, fluoro, bromo, chloro, trifluoromethyl,methoxy, ethoxy, trifluoromethoxy, and benzyl.

Preferred R⁶ and R⁷ Groups

Preferred are R⁶ and R⁷ groups independently selected from the groupconsisting of hydrogen, methyl, ethyl, propyl, pentyl, isopropyl, phenyland benzyl. Most preferred R⁶ and R⁷ are hydrogen atoms.

Preferred E Group

A most preferred E group is an oxygen atom (O).

Preferred A-ring

A preferred A-ring is a phenyl, thiophene, pyridyl, thiazole, imidazole,imidazoline, pyrazole, oxazole, or isothiazole, provided that both A andB rings are not each 5 or 6-member rings.

Preferred B-ring

A preferred B-ring is a phenyl, pyridyl, thiophene, imidazole,imidazoline, pyrazole, oxazole, isothiazole, or a thiazole ring.

Preferred Values for n and m

A preferred value for n is 0, 1, or 2.

A preferred value for m is 1 or 2 or 3.

A preferred value for y or z is 0 or 1.

A preferred value for p is 0 or 1.

A preferred value for k is 0 or 1.

A preferred value for j is 0 or 1 provided that k and j are notsimultaneously equal to 1.

A preferred compound is a compound selected from the group consistingof:

-   5-{4-[(3-Methyl-butylamino)-methyl]-phenoxy}-thiophene-2-carboxamide-   5-{4-[(3,3-Dimethyl-butylamino)-methyl]-phenoxy}-thiophene-2-carboxamide,-   5-{4-[(2-Cyclopentyl-ethylamino)-methyl]-phenoxy}-thiophene-2-carboxamide,-   5-{4-[(3-Ethyl-pentylamino)-methyl]-phenoxy}-thiophene-2-carboxamide,-   5-{4-[(Cyclohexylmethyl-amino)-methyl]-phenoxy}-thiophene-2-carboxamide,-   5-(4-{[2-(4-Fluoro-phenyl)-ethylamino]-methyl}-phenoxy)-thiophene-2-carboxamide,-   5-{2-Chloro-4-[(3-methyl-butylamino)-methyl]-phenoxy}-thiophene-2-carboxamide,-   5-{2-Chloro-4-[(3,3-dimethyl-butylamino)-methyl]-phenoxy}-thiophene-2-carboxamide,-   5-(2-Chloro-4-{[2-(4-fluoro-phenyl)-ethylamino]-methyl}-phenoxy)-thiophene-2-carboxamide,-   5-{2-Fluoro-4-[(3-methyl-butylamino)-methyl]-phenoxy}-thiophene-2-carboxamide,-   5-{4-[(3,3-Dimethyl-butylamino)-methyl]-2-fluoro-phenoxy}-thiophene-2-carboxamide,-   5-(2-Fluoro-4-{[2-(4-fluoro-phenyl)-ethylamino]-methyl}-phenoxy)-thiophene-2-carboxamide,-   5-{2-Methoxy-4-[(3-methyl-butylamino)-methyl]-phenoxy}-thiophene-2-carboxamide,-   5-(4-{[2-(4-Fluoro-phenyl)-ethylamino]-methyl}-2-methoxy-phenoxy)-thiophene-2-carboxamide,-   4-{5-[(3-Methyl-butylamino)-methyl]-thiazol-2-yloxy}-benzamide,-   3-Methoxy-4-{5-[(3-methyl-butylamino)-methyl]-thiazol-2-yloxy}-benzamide,-   4-{5-[(3,3-Dimethyl-butylamino)-methyl]-thiazol-2-yloxy}-benzamide,-   4-(5-{[2-(4-Fluoro-phenyl)-ethylamino]-methyl}-thiazol-2-yloxy)-benzamide,-   4-(5-{[2-(4-Fluoro-phenyl)-ethylamino]-methyl}-thiazol-2-yloxy)-3-methoxy-benzamide,-   4-{5-[(Cyclohexylmethyl-amino)-methyl]-thiazol-2-yloxy}-benzamide,-   2-(4-Pentylaminomethyl-phenoxy)-thiazole-5-carboxamide,-   2-{4-[(3-Methyl-butylamino)-methyl]-phenoxy}-thiazole-5-carboxamide,-   2-{4-[(3,3-Dimethyl-butylamino)-methyl]-phenoxy}-thiazole-5-carboxamide,-   2-(4-{[2-(4-Fluoro-phenyl)-ethylamino]-methyl}-phenoxy)-thiazole-5-carboxamide,-   2-{2-Chloro-4-[(3-methyl-butylamino)-methyl]-phenoxy}-thiazole-5-carboxamide,-   2-{2-Fluoro-4-[(3-methyl-butylamino)-methyl]-phenoxy}-thiazole-5-carboxamide,-   2-{2-Methyl-4-[(3-methyl-butylamino)-methyl]-phenoxy}-thiazole-5-carboxamide,-   2-{2-Methoxy-4-[(3-methyl-butylamino)-methyl]-phenoxy}-thiazole-5-carboxamide,-   4-[5-(2,6-Dimethyl-morpholin-4-ylmethyl)-thiazol-2-yloxy]-benzamide,-   4-{5-[(3-Methoxy-propylamino)-methyl]-thiazol-2-yloxy}-benzamide,-   4-{4-Chloro-5-[(3-methyl-butylamino)-methyl]-thiazol-2-yloxy}-benzamide,-   4-(5-Butylaminomethyl-4-chloro-thiazol-2-yloxy)-benzamide,-   4-{4-Chloro-5-[(3,3-dimethyl-butylamino)-methyl]-thiazol-2-yloxy}-benzamide,-   4-[5-(Phenethylamino-methyl)-thiophen-2-yloxy]-benzamide,-   4-{5-[(3-Methyl-butylamino)-methyl]-thiophen-2-yloxy}-benzamide,-   4-(5-{[2-(3-Fluoro-phenyl)-ethylamino]-methyl}-thiophen-2-yloxy)-benzamide,-   4-{5-[(2-Cyclopentyl-ethylamino)-methyl]-thiophen-2-yloxy}-benzamide,-   4-{5-[(2-Thiophen-2-yl-ethylamino)-methyl]-thiophen-2-yloxy}-benzamide,-   4-{5-[(3,3-Dimethyl-butylamino)-methyl]-thiophen-2-yloxy}-benzamide,-   3-Methoxy-4-[5-(phenethylamino-methyl)-thiophen-2-yloxy]-benzamide    hydrochloride,-   3-Methoxy-4-{5-[(3-methyl-butylamino)-methyl]-thiophen-2-yloxy}-benzamide    hydrochloride,-   4-[5-(2-Phenethylamino-ethyl)-thiophen-2-yloxy]-benzamide    hydrochloride,    or a pharmaceutically acceptable salt, solvate, enantiomer,    diastereomer and diastereomric mixture thereof.

A more preferred compound of the invention is a compound selected fromthe group consisting of:

-   4-[5-(Phenethylamino-methyl)-thiophen-2-yloxy]-benzamide

-   4-{5-[(3-Methyl-butylamino)-methyl]-thiophen-2-yloxy}-benzamide

-   4-(5-{[2-(3-Fluoro-phenyl)-ethylamino]-methyl}-thiophen-2-yloxy)-benzamide

-   4-{5-[(2-Cyclopentyl-ethylamino)-methyl]-thiophen-2-yloxy}-benzamide

-   4-{5-[(2-Thiophen-2-yl-ethylamino)-methyl]-thiophen-2-yloxy}-benzamide

-   4-{5-[(3,3-Dimethyl-butylamino)-methyl]-thiophen-2-yloxy}-benzamide

-   3-Methoxy-4-[5-(phenethylamino-methyl)-thiophen-2-yloxy]-benzamide    hydrochloride

-   3-Methoxy-4-{5-[(3-methyl-butylamino)-methyl]-thiophen-2-yloxy}-benzamide    hydrochloride

-   4-[5-(2-Phenethylamino-ethyl)-thiophen-2-yloxy]-benzamide    hydrochloride

-   5-{4-[(3-Ethylpentylamino)methyl]phenoxy}thiophene-2-carboxamide

-   2-{4-[(3-Methylbutylamino)methyl]phenoxy}thiazole-5-carboxamide

-   2-(4-{[2-(Tetrahydropyran-4-yl)ethylamino]methyl}phenoxy)thiazole-5-carboxamide

methanesulfonate

and a pharmaceutically acceptable salt, solvate, enantiomer,diastereomer or diastereomeric mixture thereof.

Making Compounds of the Invention

In a typical protocol, an optionally substituted carbaldehyde, e.g., thethiophene carbaldehyde, 5-bromo-thiophene-2-carbaldehyde (1) where X isbromo or synthon thereof, is employed.

A shown in scheme 1, optionally substituted5-halo-thiophene-2-carbaldehyde 1 (wherein X is halogen) is reacted withoptionally substituted 4-hydroxybenzonitrile (2) to afford the ether 3,under basic reaction conditions. Basic reaction conditions include theuse of bases selected from inorganic and organic bases. Examples ofuseful inorganic bases include but are not limited to potassiumcarbonate, sodium carbonate, sodium hydroxide, potassium hydroxide,calcium carbonate, and cesium carbonate. Examples of organic basesinclude but are not limited to potassium hexamethyl disilazide, n-butyllithium, sodium hydride, hexamethylphosphorous triamide, (HMPT), and thelike. The basic conditions are complemented by the presence of asolvent, preferably an organic solvent. Preferred organic solventsinclude protic solvents or polar aprotic solvents. Most preferredsolvents include DMA (dimethylacetamide) dimethylformamide, methanol,dimethylsulfoxide. A most preferred basic reaction condition involvesthe use of potassium carbonate in dimethylacetamide at temperatures fromabout 80-100° C. Certain reactions may require refluxing conditionswhile others may require lower temperatures depending on the particularsubstrates.

The nitrile compound 3 is converted to the carboxamide 4 by hydrolysisprocedures known to one of skill in the art. For example, the compound 3is reacted with potassium carbonate or other suitable base in thepresence of hydrogen peroxide in a suitable organic solvent i.e. DMSO orDMF. The resulting amide compound 4 is reductively aminated with asuitably substituted amine. The reductive amination may be performed intwo steps or a single step depending on the stability of theintermediate imine. Typically, the compound 4 is reacted with a primaryor secondary amine in methanol as solvent. Molecular sieves may be addedto enhance the efficiency of the amination reaction. In a second step,the reducing agent, typically, sodium borohydride or other hydridereducing agent is added to the reaction mixture. The progress of thereaction may be monitored by TLC, HPLC, HPLC-MS or other analyticaltechnique known to one of skill in the art to determine the substantialcompletion of each step and timing for the addition of the next reagent.The reductive amination of compound 4 results in the compound of formula5, which is itself a compound of the invention. Analogues of compounds 3and 5 having one or more substituent R groups may be prepared by usingappropriately substituted starting materials or by inter-conversion ofsubstituent functionality, that is, converting a substituent amenable tointermediate reactions i.e. converting a protected group or synthon tothe desired substituent in a later step.

An alternate protocol illustrated by Scheme 2 is the use of thecarboxamide starting material to prepare, for example, compounds whereinthe B-ring is a thiophenyl ring or similar five-member heterocyclicring.

The use of the carboxamide starting material is particularly preferredfor compounds of the invention where the B-ring is thiophenyl, orthiazolyl group. The carboxamide may be introduced as part of thestarting material where the appropriate surrogate for the B-ring iscommercially available, or may be prepared by known procedures or knownmodifications thereof. The initially formed ether is reductivelyaminated at the aldehyde functionality to afford the amine product(Scheme 2).

A modified protocol is provided in Scheme 3 wherein the nucleophilicdisplacement reaction to form the ether linkage is performed afterinstallation of the amino sidechain.

Under this protocol an appropriately substituted aminophenol isreductively aminated with an optionally substituted benzaldehyde. Thereductive amination is accomplished in the presence of sodiumborohydride or other reducing agent and a suitable base.Tertiary-butoxycarbonyl anhydride (Boc-anhydride) is used to affordprotection of the incipient free amine as the Boc-protected amine. Theresulting phenoxy compound 7 is then reacted with a B ring source suchas for example, an appropriately substituted or unsubstituted halogenothiophenyl nitrile or carboxamide or synthon thereof. The coupling ofthe B and A-ring sources is performed under basic conditions to affordthe ether 8 for the above example. In the next step, the nitrile group,if present as in the current example, is hydrolyzed to the carboxamideas discussed previously. The protecting group may be removed by use oftrifluoroacetic acid or hydrochloric acid using procedures known to oneof skill in the art. One of skill in the art is aware that appropriatelysubstituted analogs of the compound 10 may be prepared by starting withappropriately substituted starting materials or surrogates thereof whichmay be converted to the desired substituents.

Compounds of formula I having varying alkyl chain lengths on the aminoside chain may be prepared in one instance by carbonyl elongationreactions. An example is a modified Wittig type reaction as shown inScheme 4.

The protocol of Scheme 4 and known variations thereof, allowmanipulation of the amino side chain for chain length and/orsubstituents. Under this protocol, optionally substituted4-hydroxybenzaldehyde e.g. compound 11 is reacted with an optionallysubstituted 5-membered ring nitrile compound having a suitable leavinggroup, e.g. 5-chloro-2-cyanothiophene. The product 12 or analog thereof,is then subjected to a carbonyl elongation reaction such as, forexample, the Wittig reaction and variations thereof. (seeOrganophosporus agents in organic Synthesis, J. I. G. Cadogan, Ed.,Academic Press London (1979); see also, J. March, Advanced OrganicChemistry, 3^(rd) Edition, Wiley Interscience, New York N.Y., (1995). Inthe example given, the aldehyde 12 is reacted withmethoxymethyltriphenylphosphonium chloride (available from Aldrichchemical Company, Milwaukee, USA) using a strong base such as, forexample, KHMDS (potassium hexamethyl disilizade), n-butyl lithium,sec-butyl lithium and the like, to generate the incipient carbanion. Theresulting vinylmethyl ether 13 is hydrolyzed using a strong acid, e.g.,p-toluenesulfonic acid, HCl or sulfuric acid to generate the newaldehyde 13a. The aldehyde 13a is then reacted with a suitable aminefollowed by reduction to afford the reductive amination product 14.Details of each step in the schemes disclosed herein are provided in theexperimental section, or may be found in reference organic synthesistexts or are known to one of skill in the art. Some reactions such asthe formation of the ylide specie for the Wittig and related reactionsperform better at reduced temperatures ranging from about −10° C. toabout −80° C. Other reactions perform better at elevated temperaturesranging from about 30° C. to about 150° C., and yet other reactionsperform better at ambient temperature ranging from about 15° C. to about30° C.

Compounds of the invention wherein the groups R¹ and R² combine witheach other and with the nitrogen atom to which they are attached to forma nitrogen containing heterocycle, may be prepared, for example,according to scheme 5.

According to Scheme 5, the reductive amination of aldehyde with amine isperformed using a cyclic amine having the desired ring size and/orsubstituents. For example, the reaction of an optionally substitutedcyclic amine i.e. optionally substituted pyrrolidine (shown) with thealdehyde 4 results in the formation of compound 17 wherein R¹ and R²combine to form the nitrogen containing heterocyclic amine. The startingmaterial 2-chloro-5-cyanothiophene 16 may be prepared from thecorresponding carboxamide (2-carboxamido-5-chlorothiophene), which inturn may be prepared from the corresponding carboxylic acid analog, i.e.5-chlorothiophene-2-carboxylic acid. Procedures for converting thecarboxylic acid derivative to the carboxamide followed by dehydration toform the nitrile 16 are known to one of skill in the art, are disclosedin general organic reference texts, or are disclosed partially or intotal in the experimental section herein.

Similarly, compounds of formula I having 5-member heterocyclic ringsother than thiophene, may be prepared as shown in Scheme 6 (for thiazolecompounds) by using other appropriately substituted 5-member ringreagents.

As shown above, nucleophilic displacement reaction of appropriatelysubstituted 2-halothiazole compound 17a on an optionally substitutedhydroxy benzaldehyde affords the ether 18. The cyano group of the ether18 is then hydrolyzed under basic conditions such as in the presence ofpotassium carbonate and hydrogen peroxide as promoter to afford thecarboxamide 19. The carboxamide 19 is reductively aminated to the amine20. The hydroxy benzaldehyde compound or optionally substituted analogsor positional isomers thereof may be obtained from commercial sources ormay be prepared from commercially available starting materials.Similarly, the thiazolyl compounds i.e. compound 17a may be preparedfrom the corresponding lithio or halo thiazole compound or synthonsthereof. For example, the starting material2-chloro-1,3-thiazole-5-carbonitrile may be prepared from2-chloro-1,3-thiazole-5-carboxylic acid which may be purchased fromBionet Research Limited, Cornwall, PL329QZ, United Kingdom.

In another embodiment of the processes for making compounds of theinvention, the amino side chain may be introduced as a pre-installedsubstituent on the A ring. For example, Scheme 7 shows the preparationof certain compounds of the invention wherein the amino side chain isintroduced as part of the starting material constituting the A-ring.

In Scheme 7, the starting material,2-chloro-thiazol-5-yl-methyl)-(3-methoxy-propyl)-amine (21), may bepurchased from Key Organics Limited/Bionet Research, Cornwall, UK.Analogs of the above starting material may be similarly purchased orprepared using known procedures. Reaction conditions and procedures forthe coupling reaction and the subsequent hydrolysis of the nitrile tothe amide have been disclosed in the experimental section and are alsoknown to one of skill in the art.

Analogous to the procedure of Scheme 7, compounds wherein the R¹ and R²groups combine to form a nitrogen containing heterocycle may also beprepared using pre-installed cyclic amine groups on the A-ring as shownfor example in Scheme 8.

In an alternate procedure the thiazole starting material may be preparedas shown in Scheme 9 or knonwn variationn thereof.

The preparation and use of the thiazole starting mateial according toscheme 9 begins with an aldol condensation of ethylfromate andethylchloroacetate. The intermediate aldol condensation product isreacted with thiourea to afford the aminothiazole compound (27). Thereaction is performed at temperatures ranging from about 70 to 90° C.The amino thaizole (27) is converted to the chlorothiazole compounddiazoltization followed by chlorination as in the Sandmeyer reaction(see Name Reactions and Reagents in Organic Synthesis by Bradford P.Mundy and Michael Ellerd, John Wiley and Sons Publishers, New York, N.Y.1988.) The resulting chlorothiazole ethyl ester (28) is aminated bybubbling excess ammonia into a cold methanolic solution of 28 to affordthe carboxamide (29). The reaction is performed in a pressure vessaeland may be heated to about 30 to 60° C. for 1 to 4 hours or asappropriate for complete reaction. The use of molecular sieves has alsobeen found to facilitate the reactionat lower temperatures. Thecarboxamido chlorothiazole (29) is then reacted with, for example,4-hydroxybenzaldehyde to afford the ether linkage. Depending on the ringdesired, and appropriately substituted hydroxy carbaldehyde compoundbearing the desired ring may be used to afford the ether linkage. Theformation of the ether linkage has been discussed previously. The ethercompound (30) may be reductively aminated at the carbonyl group with adesired amine compound e.g., isopentyl amine, to afford the desiredcompound (31).

The above procedures and minor modifications known to one of skill inthe art are useful to prepapre other compounds of the invention.

Method of Using the Invention

As noted above, the compounds of the present invention are useful inblocking the effect of agonists at mu, kappa, and/or delta opioidreceptors. As such, the present invention also provides a method forblocking a mu, kappa, delta receptor or receptor combination(heterodimer) thereof in mammals comprising administering to a mammalrequiring blocking of a mu, kappa, delta or combinations of mu, kappa,and/or delta receptors, a receptor blocking dose of a compound offormula I.

The term “receptor blocking dose”, as used herein, means an amount of acompound of formula I necessary to effectively block a mu, kappa, ordelta receptor or receptor combination (heterodimer) thereof followingadministration to a mammal requiring blocking of a mu, kappa, or deltareceptor or receptor combination (heterodimer) thereof.

The compounds of formula I or combinations thereof, are effective over awide dosage range. For example, dosages per day will normally fallwithin the range of about 0.05 to about 50 mg/kg of body weight. In thetreatment of adult humans, the range of about 0.5 to about 50 mg/kg, insingle or divided doses, is preferred. However, it will be understoodthat the amount of the compound actually administered will be determinedby a physician in light of the relevant circumstances, including thecondition to be treated, the choice of compound to be administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the chosen route of administration, andtherefore the above dosage ranges are not intended to limit the scope ofthe invention in any way. The compound(s) of the invention may beadministered by a variety of routes such as the oral, transdermal,subcutaneous, sublingual, intranasal, intramuscular or intravenousroutes.

A variety of physiologic functions have been shown to be subject to orinfluenced by mu, kappa, or delta receptors or receptor combination(heterodimers) in the brain. As such, the compounds of the presentinvention are believed to have the ability to treat a variety ofdisorders in mammals associated with these receptors or combinationsthereof, such as eating disorders, opioid overdose, depression, smoking,alcoholism, sexual dysfunction, shock, stroke, spinal damage and beadtrauma. As such, the present invention also provides methods of treatingthe above disorders by blocking the effect of agonists at a mu, kappa,delta receptor or receptor combination (heterodimer) thereof.

The compounds of the present invention have been found to displaysignificant activity in an opioid receptor binding assay which measuresthe ability of the compounds to block the mu, kappa, delta or receptorcombination (heterodimer) thereof.

GTP-γ-S Binding Assay

A scintillation proximity assay (SPA)-based GTP-γ-S³⁵ assay format wasdeveloped based on previous opioid (Emmerson et al., J. Pharm Exp Ther278, 1121, 1996; Horng et al., Society for Neuroscience Abstracts,434.6, 2000) and muscarinic (DeLapp et al., JPET 289, 946, 1999) assayformats. Membranes were resuspended in 20 mM HEPES, 100 mM NaCl, 5 mMMgCl2, 1 mM DTT, and 1 mM EDTA. Fifty mL of GTP-γ-[35S], compound,membrane suspension (20 microgram/well), and wheat germ agglutinincoated SPA beads (1 mg/well) were added to clear bottom 96 well assayplates. GDP (200 mM) was added to the membrane solution prior toaddition to the assay plates. Plates were sealed and incubated for fourhours at room temperature then placed in a refrigerator overnight toallow the beads to settle. Signal stability at 4° C. was determined tobe >60 hours. Plates were warmed to room temperature and counted in aWallac Microbeta scintillation counter. For antagonist assays, specificagonists were added at the following concentrations: (MOR) DAMGO 1micromolar, (DOR) DPDPE 30 nM, (KOR) US69593 300 nM. Kb's weredetermined by Cheng-Prusoff equation (see Cheng and Prusoff, Biochem.Pharmacol. 22, 3099 1973).

TABLE 1 In Vitro Antagonism GTP-γ-S Kb (nM) Example No. Mu Kappa Delta 10.6 4.6 3.3 2 3.7 2.2 19.4 3 0.6 3.9 1.6 4 0.6 1.0 2.7 5 0.6 1.4 2.4 65.7 — 13.7 7 0.3 4.0 1.3 8 4.7 3.2 40.5

Formulation

A compound of the invention is preferably presented in the form of apharmaceutical formulation comprising a pharmaceutically acceptablecarrier, diluent or excipient and a compound of the invention. Suchcompositions will contain from about 0.1 percent by weight to about 90.0percent by weight of the compound of the invention (Active Ingredient).As such, the present invention also provides pharmaceutical formulationscomprising a compound of the invention and a pharmaceutically acceptablecarrier, diluent or excipient therefor.

In making the compositions of the present invention, the activeingredient will usually be mixed with a carrier, or diluted by acarrier, or enclosed within a carrier which may be in the form of acapsule, sachet, paper or other container. When the carrier serves as adiluent, it may be a solid, semi-solid or liquid material that acts as avehicle, excipient or medium for the active ingredient. Thus, thecomposition can be in the form of tablets, pills, powders, lozenges,sachets, cachets, elixirs, emulsions, solutions, syrups, suspensions,aerosols (as a solid or in a liquid medium) and soft and hard gelatincapsules.

Examples of suitable carriers, excipients, and diluents include lactose,dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calciumphosphate, alginates, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, tragacanth, gelatin, syrup, methylcellulose, methyl- and propylhydroxybenzoates, talc, magnesium stearate,water, and mineral oil. The formulations may also include wettingagents, emulsifying and suspending agents, preserving agents, sweeteningagents or flavoring agents. The formulations of the invention may beformulated so as to provide quick, sustained, or delayed release of theactive ingredient after administration to the patient by employingprocedures well known in the aft.

For oral administration, the Active Ingredient, a compound of thisinvention ideally can be admixed with carriers and diluents and moldedinto tablets or enclosed in gelatin capsules.

The compositions are preferably formulated in a unit dosage form, eachdosage containing from about 1 to about 500 mg, more usually about 5 toabout 300 mg, of the Active Ingredient. The term “unit dosage form”refers to physically discrete units suitable as unitary dosages forhuman subjects and other mammals, each unit containing a predeterminedquantity of active material calculated to produce the desiredtherapeutic effect, in association with a suitable pharmaceuticalcarrier.

In order to more fully illustrate the operation of this invention, thefollowing formulation examples are provided. The examples areillustrative only, and are not intended to limit the scope of theinvention. The formulations may employ as Active Ingredient any of thecompounds of the present invention.

FORMULATION 1 Hard gelatin capsules are prepared using the followingingredients: Amount per Concentration Compound capsule (mg) by weight(%) Active Ingredient 250 55 Starch dried 200 43 Magnesium stearate 10 2

The above ingredients are mixed and filled into hard gelatin capsules in460 mg quantities.

FORMULATION 2 Capsules each containing 20 mg of medicament are made asfollows: Amount per Concentration Compound capsule (mg) by weight (%)Active Ingredient 20 10 Starch 89 44.5 Microcrystalline cellulose 8944.5 Magnesium stearate 2 1

The active ingredient, cellulose, starch and magnesium stearate areblended, passed through a No. 45 mesh U.S. sieve and filled into a hardgelatin capsule.

FORMULATION 3 Capsules each containing 100 mg of active ingredient aremade as follows: Amount per Concentration Compound capsule (mg) byweight (%) Active Ingredient 100 30 Polyoxyethylene Sorbitan monooleate50 mcg 0.02 Starch powder 250 69.98

The above ingredients are thoroughly mixed and placed in an emptygelatin capsule.

FORMULATION 4 Tablets each containing 10 mg of active ingredient areprepared as follows: Amount per Concentration Compound capsule (mg) byweight (%) Active Ingredient 10 10 Starch 45 45 Microcrystallinecellulose 35 35 Polyvinylpyrrolidone 4 4 (as 10% solution in water)Sodium carboxymethyl starch 4.5 4.5 Magnesium stearate 0.5 0.5 talc 1 1

The active ingredient, starch and cellulose are passed through a No. 45mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders which are thenpassed through a No. 14 mesh U.S. sieve. The granule so produced isdried at 50-60° C. and passed through a No. 18 mesh U.S. sieve. Thesodium carboxymethyl starch, magnesium stearate and talc, previouslypassed through a No. 60 mesh U.S. sieve, are then added to the granulewhich, after mixing, is compressed on a tablet machine to yield a tabletweighing 100 mg.

FORMULATION 5 A tablet formula may be prepared using the ingredientsbelow: Amount per Percent Compound capsule (mg) by weight (%) ActiveIngredient 250 38 Cellulose microcrystalline 400 60 Silicon dioxidefumed 10 1.5 Stearic acid 5 0.5

The components are blended and compressed to form tablets each weighing665 mg.

FORMULATION 6 Suspensions each containing 5 mg of medicament per 5 mldose are made as follows: Amount per 5 mL Compound suspension (ml)Active Ingredient 5 Sodium carboxymethyl cellulose 50 Syrup 1.25 Benzoicacid solution 0.10 Flavor q.v. Color q.v. Water q.s. to 5 mL

The medicament is passed through a No. 45 mesh U.S. sieve and mixed withthe sodium carboxymethylcellulose and syrup to form a smooth paste. Thebenzoic acid solution, flavor and color is diluted with some of thewater and added to the paste with stirring. Sufficient water is thenadded to produce the required volume.

FORMULATION 7 An aerosol solution is prepared containing the followingcomponents: Concentration Compound by weight (percent) Active Ingredient0.25 Ethanol 29.75 Propellant 22 (chlorodifluoromethane) 70.0

The active compound is mixed with ethanol and the mixture added to aportion of the Propellant 22, cooled to −30° C. and transferred to afilling device. The required amount is then fed to a stainless steelcontainer and diluted further with the remaining amount of propellant.The valve units are then fitted to the container.

EXAMPLE 1 4-[5-(Phenethylamino-methyl)-thiophen-2-yloxy]-benzamide

Part A, Method A:Preparation of 4-(5-Formyl-thiophen-2-yloxy)-benzonitrile

Combine 4-hydroxybenzonitrile (1.89 g, 15.07 mmol), sodium hydride (603mg, 15.07 mmol) and DMSO (25 mL). Stir for 5-10 min at rt, then add5-bromothiophene-2-carbaldehyde (1.5 mL, 12.56 mmol). Stir the reactionmixture at 100° C. overnight. Cool the reaction mixture to roomtemperature, then pour into water and extract thoroughly with diethylether (2×15 mL). Dry the organic layers over magnesium sulfate, filterand concentrate. Purify the crude product through flash chromatographyusing CH₂Cl₂/hexanes (2/1) as eluent to provide 500 mg (17%) of thetitle compound.

Part A, Method B:

Combine 4-hydroxybenzonitrile (1.37 g, 11.5 mmol), cesium carbonate (5.1g, 15.69 mmol) and dimethylacetamide (DMA) (52 mL). Stir for 5 minutesat room temperature, and then add 5-bromothiophene-2-carbaldehyde (1.25mL, 10.5 mmol). Stir the reaction mixture at 100° C. overnight. Cool thereaction mixture to room temperature, then pour into water and extractthorough with diethyl ether (2×30 mL). Dry the organic layers overmagnesium sulfate, filter and concentrate. Purify the product throughflash chromatography using CH₂Cl₂/hexanes (2/1) as eluent to provide 772mg (32%) of the title compound.

Part B, Method A

Preparation of4-[5-(Phenethylamino-methyl)-thiophen-2-yloxy]-benzonitrile

Combine 4-(5-formyl-thiophen-2-yloxy)-benzonitrile (200 mg, 0.87 mmol),(MeO)₃CH (1.2 mL), phenethyl amine (0.142 mL, 130 mol %) and methanol(1.7 mL). Stir the resulting mixture for 3 hours, and then add sodiumborohydride in portions. Stir for few hours. Then, concentrate to removethe methanol. Partition the resulting residue between H₂O (5 mL) andCH₂Cl₂ (7 ml). Dry the organic layer over sodium sulfate, filter andconcentrate. Purify the product through flash chromatography[CH₂Cl₂/Ammonia (2.0 M in methanol) 20/1] to provide the title compound(139 mg, 48%).

Part C, Method A

Combine 4-[5-(phenethylamino-methyl)-thiophen-2-yloxy]-benzonitrile((139 mg, 0.415 mmol), K₂CO₃ (powder, 28 mg, 50 mol %) and DMSO (4 mL).Cool down to 0° C. Add hydrogen peroxide (0.124 mL) dropwise. Stir theresulting reaction mixture for 2.5 h. Partition the reaction mixturebetween H₂O (5 mL) and CH₂Cl₂ (3×5 mL). Dry over sodium sulfate, filterand concentrate. Purify the residue through an SCX column with ammonia(2.0 M in methanol) to provide 105 mg (75%) of the title compound. Massspectrum (ion spray): m/z=353.0 (M+1). ¹H NMR (Cl₃CD): 7.80 (d, J=8.7Hz, 2H), 7.34-7.22 (m, 5H), 7.12 (d, J=8.7 Hz, 2H), 6.65 (d, J=3.37 Hz,1H), 6.44 (d, J=3.7 Hz, 1H), 5.96 (bs, 2H), 3.93 (s, 2H), 2.97 (t, J=6.4Hz, 2H), 2.85 (t, J=6.5 Hz, 2H).

Part B, Method B

Preparation of 4-(5-Formyl-thiophen-2-yloxy)-benzamide

Combine 4-(5-formyl-thiophen-2-yloxy)-benzonitrile (772 mg, 3.36 mmol),K₂CO₃ (powder, 232 mg, 50 mol %) and DMSO (33 mL). Cool down to 0° C.Add hydrogen peroxide (1.01 mL) dropwise. Stir the resulting reactionmixture for 3 hours. Pour the reaction mixture onto H₂O (5 mL). Stir for5 min till a white precipitate appears, then filter and dry under vacuumto provide 633 mg (76%) of the title compound. Part C would be thereaction of this intermediate with an amine to make the final compound.Example 1 was prepared using Method A; Example 2 used Medthod B.

EXAMPLE 24-{5-[(3-Methyl-butylamino)-methyl]-thiophen-2-yloxy}-benzamide

Combine 4-(5-formyl-thiophen-2-yloxy)-benzamide (99 mg, 0.40 mmol) fromExample 1 part B, method B, with 3-methyl-butylamine (0.056 mL, 0.48mmol), methyl orthoformate (0.53 mL) and methanol (0.8 mL). Stir theresulting mixture for 3 hours and then add sodium borohydride inportions. Let stir for few hours. Then, concentrate to remove themethanol. Partition the resulting residue between H₂O (4 mL) and CH₂Cl₂(6 ml). Dry the organic layer over sodium sulfate, filter andconcentrate. Purify through flash chromatography [CH₂Cl₂/Ammonia (2.0 Min methanol) 20/1] to provide the title compound.

EXAMPLE 34-(5-{[2-(3-Fluoro-phenyl)-ethylamino]-methyl}-thiophen-2-yloxy)-benzamide

Combine 4-(5-formyl-thiophen-2-yloxy)-benzamide (90 mg, 0.36 mmol) fromExample 1, part B, method B, with 2-(3-fluoro-phenyl)-ethylamine (61 mg,0.44 mmol), methyl orthoformate (0.48 mL) and methanol (0.7 mL). Stirthe resulting mixture for 3 hours and then add sodium borohydride inportions. Stir the reactiom misture until the reaction is complete byTLC or HPLC analyses. Then, concentrate to remove the methanol.Partition the resulting residue between H₂O (4 mL) and CH₂Cl₂ (6 ml).Dry the organic layer over sodium sulfate, filter and concentrate.Purify through flash chromatography [CH₂Cl₂/Ammonia (2.0 M in methanol)20/1] to provide the title compound. ¹H NMR (CDCl₃): 7.72 (d, J=8.7 Hz,2H), 7.21-7.13 (m, 1H), 7.03 (d, J=8.7 Hz, 2H), 6.92-6.80 (m, 3H), 6.56(d, J=3.6 Hz, 1H), 6.36 (d, J=3.7 Hz, 1H), 5.82 (bs, 2H), 3.83 (s, 2H),2.87 (t, J=6.5 Hz, 2H), 2.75 (t, J=6.6 Hz, 2H).

EXAMPLE 44-{5-[(2-Cyclopentyl-ethylamino)-methyl]-thiophen-2-yloxy}-benzamide

Using a method similar to Example 2, using 2-cyclopentyl-ethylamine (49mg, 0.437 mmol) gives the title compound. ¹H NMR (CDCl₃): 7.82 (d, J=8.7Hz, 2H), 7.14 (d, J=8.7 Hz, 2H), 6.79 (d, J=3.3 Hz, 1H), 6.49 (d, J=3.7Hz, 1H), 6.47 (bs, 2H), 3.92 (s, 2H), 2.80-2.67 (m, 2H), 1.79-1.54 (m,9H).

EXAMPLE 54-{5-[(2-Thiophen-2-yl-ethylamino)-methyl]-thiophen-2-yloxy}-benzamide

Using a method similar to Example 2, using 2-thiophen-2-yl-ethylamine(55 mg, 0.436 mmol) gives the title compound. ¹H NMR (CDCl₃): 7.71 (d,J=8.7 Hz, 2H), 7.08-7.02 (m, 3H), 6.87-6.85 (m, 1H), 6.77 (d, J=2.8 Hz,1H), 6.58 (d, J=3.5 Hz, 1H), 6.36 (d, J=3.6 Hz, 1H), 5.80 (bs, 2H), 3.85(s, 2H), 2.97-2.90 (m, 4H).

EXAMPLE 64-{5-[(3,3-Dimethyl-butylamino)-methyl]-thiophen-2-yloxy}-benzamide

Using a method similar to Example 2, using 3,3-dimethyl-butylamine(0.049 mL, 0.361 mmol) gives the title compound (87 mg, 76%). m/z=232.0(M+1). ¹H NMR (DMSO-d₆): 7.90 (bs, 3H), 7.30 (s, 1H), 7.1 (bs, 2H), 6.72(s, 1H), 6.55 (s, 1H), 3.78 (s, 2H), 3.32 (s, 2H), 1.32 (s, 2H), 0.85(s, 9H).

EXAMPLE 73-Methoxy-4-[5-(phenethylamino-methyl)-thiophen-2-yloxy]-benzamidehydrochloride

Step 1Preparation of 4-(5-Formyl-thiophen-2-yloxy)-3-methoxy-benzonitrile

Using a method similar to preparation of the compound of Example 1 partA, method A, and using 4-hydroxy-3-methoxy-benzonitrile (859 mg, 5.76mmol) gives the title compound (225 mg, 17%). ¹H NMR (Cl₃CD): 9.71 (s,1H), 7.54 (d, J=4.1 Hz, 1H), 7.30 (d, J=8.1 Hz, 1H), 7.28 (s, 1H), 7.23(d, J=8.1 Hz, 1H), 6.53 (d, J=4.2 Hz, 1H), 3.89 (s, 3H).

Step 2

Preparation of 4-(5-Formyl-thiophen-2-yloxy)-3-methoxy-benzamide

Using a method similar to example 1, part B, method B, and using4-(5-formyl-thiophen-2-yloxy)-3-methoxy-benzonitrile (225 mg, 0.867mmol) gives the title compound.

Step 3

Using a method similar to Example 2, using phenethylamine (0.082 mL,0.649 mmol) and 4-(5-formyl-thiophen-2-yloxy)-3-methoxy-benzamide (150mg, 0.54 mmol) gives the title compound. ¹H NMR (MeOH-d₄): 7.62 (d,J=1.9 Hz, 1H), 7.47 (dd, J=1.9 and 8.4 Hz, 1H), 7.32-7.19 (m, 5H), 7.10(d, J=8.3 Hz, 1H), 6.78 (d, J=3.7 Hz, 1H), 6.39 (d, J=3.8 Hz, 1H), 3.99(s, 2H), 3.91 (s, 3H), 2.99-2.84 (m, 4H).

EXAMPLE 83-Methoxy-4-{5-[(3-methyl-butylamino)-methyl]-thiophen-2-yloxy}-benzamidehydrochloride

Using a method similar to Example 2, using 3-methyl-butylamine (0.050mL, 0.432 mmol) and 4-(5-formyl-thiophen-2-yloxy)-3-methoxy-benzamide(100 mg, 0.36 mmol) gives the title compound. ¹H NMR (DMSO-d₆): 7.65 (d,J=1.9 Hz, 1H), 7.49 (dd, J=1.9 and 8.3 Hz, 1H), 7.22 (bd, 1H), 7.17 (d,J=8.3 Hz, 1H), 7.01 (d, J=3.9 Hz, 1H), 6.99 (bd, 1H), 6.45 (d, J=3.9 Hz,1H), 4.31 (bs, 2H), 3.91 (s, 3H), 3.31 (m, 2H), 1.62-1.57 (m, 3H), 0.97(d, J=6.4 Hz, 6H).

EXAMPLE 9 4-[5-(2-Phenethylamino-ethyl)-thiophen-2-yloxy]-benzamidehydrochloride

Step 1Preparation of 4-[5-(2-Oxo-ethyl)-thiophen-2-yloxy]-benzonitrile

Combine a solution of methoxy methyl triphenyl phosphonium chloride (358mg, 1.047 mmol) in THF (3.6 mL) with a solution of KHMDS (0.5M intoluene, 2 mL, 1.047 mmol) at 0° C. for 20-40 min. Cool the resultingorange solution to about −78° C., then add a solution of4-(5-formyl-thiophen-2-yloxy)-benzonitrile in THF (1 mL) dropwise overabout 10 min. Stir at about −78° C. for 45 min, then allow the reactionmixture to warm to room temprature and quench with H₂O (5 mL). Extractthe reaction mixture with ether (5 mL), wash with H₂O, dry overmagnesium sulfate, filter and concentrate. Purify the crude product byflash chromatography (CH₂Cl₂) to provide 155 mg of4-[5-(2-methoxy-vinyl)-thiophen-2-yloxy]-benzonitrile. Redissolve theproduct in i-PrOH (about 0.8 mL)—H₂O (about 0.8 mL) and add pTsOH.H₂O (4mg, 0.018 mmol). Stir the reaction mixture at reflux for 2-3 hours. Coolthe reaction mixture to room temprature, dilute with H₂O (5 mL) andextract with diethyl ether (6 mL). Wash the organic layer with sodiumbicarbonate, brine, dry over magnesium sulfate, filter and concentrateunder reduced pressure to give the title compound.

Step 2

4-[5-(2-Phenethylamino-ethyl)-thiophen-2-yloxy]-benzonitrile

Using a method similar to preparation of the compound of Example 1 partB, method A, and using phenethyl amine (0.022 mL, 0.17 mmol) gives thetitle compound (25 mg, 55%).

Step 3

4-[5-(2-Phenethylamino-ethyl)-thiophen-2-yloxy]-benzamide hydrochloride

Using a method similar to Example 1, and using4-[5-(2-phenethylamino-ethyl)-thiophen-2-yloxy]-benzonitrile (25 mg,0.072 mmol) gives the title compound as the free base. Treatment withHCl (1M in ether) provides the hydrochloride salt.

EXAMPLE 105-{4-[(3-Methylbutylamino)methyl]phenoxy}thiophene-2-carboxamide

Part A: 5-Fluorothiophene-2-carbonitrile

Reference: Chambers, R. J.; Marfat, A. Synth. Commun., 2000, 30 (19),3629-3632.

Mix 2-cyano-5-nitrothiophene (1.000 g, 6.49 mmol), spray dried KF (1.885g, 32.43 mmol), tetraphenylphosphonium bromide (0.250 g, 0.597 mmol) andphthaloyl dichloride (0.935 mL-6.49 mmol) in sulfolane (20 mL) and heatat 180° C. After two hours, cool to room temperature, then dilute withwater (100 mL) and extract with ether (3×100 mL). Wash the extract with1.0 N NaOH (1×50 mL) and brine (1×50 mL). Dry the organic layer overMgSO₄, filter and concentrate. Purify by chromatography eluting with 10%EtOAc in hexanes to give the title compound: ¹H NMR (CDCl₃): 7.33 (t,J=4.0 Hz, 1H), 6.56 (dd, J=4.4, 1.8 Hz, 1H); HPLC [YMC-Pro pack C-18(150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at1.0 mL/min, 30-99% over 18 min], t_(R)=7.3 min, 94.1% purity.

Part B: 5-(4-Formylphenoxy)thiophene-2-carbonitrile

Dissolve 5-fluorothiophene-2-carbonitrile (0.541 g, 4.25 mmol) and4-hydroxybenzaldehyde (0.519 g, 4.25 mmol) in DMF (11 mL). Add K₂CO₃(1.469 g, 10.6 mmol) and heat at 100° C. for 1.5 hours. Concentrate thereaction mixture. Take the solid up in ethyl acetate (100 mL) and washwith water (2×25 mL). Dry the organic layer over MgSO₄, filter andconcentrate. Purify by chromatography eluting with 30% ethyl acetate inhexanes to give the title compound: ¹H NMR (CDCl₃): 9.96 (s, 1H), 7.98(dd, J=6.6, 2.2 Hz, 2H), 7.86 (d, J=4.0 Hz, 1H), 7.40 (d, J=2.2 Hz, 2H),6.96 (d, J=4.0 Hz, 1H); HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20%over 5 min, 20-95% over 18], t_(R)=17.4 min, 98.1% purity.

Part C: 5-(4-Formylphenoxy)thiophene-2-carboxamide

Dissolve 5-(4-formylphenoxy)thiophene-2-carbonitrile (0.818 g, 3.57mmol) in DMSO (18 mL) in a round bottom flask, then add K₂CO₃ (0.247 g,1.78 mmol). Cool the reaction flask in a water bath and add 30% H₂O,(0.81 mL, 7.14 mmol) solution. After one hour, add water (25 mL). Filterthe resulting precipitate and wash the filter cake with water (25 mL).Collect the filter cake as the title compound: HRMS calcd for C₁₂H₁₀NO₃S248.0381 (M+H)⁺, found 248.0396, time 0.36 min; HPLC [YMC-Pro pack C-18(150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at1.0 mL/min, 10-20% over 5 min, 20-95% over 18], t_(R)=13.0 min, 100%purity.

Part D: 5-{4-[(3-Methylbutylamino)methyl]phenoxy}thiophene-2-carboxamide

Place 5-(4-formylphenoxy)thiophene-2-carboxamide (0.235 g, 0.948 mmol),isoamylamine (0.087 g, 0.996 mmol) and 3 Å molecular sieves in a vial.Add methanol (4.7 mL), cap and stir overnight. Add NaBH₄ (0.0359 g,0.948 mmol) and stir until the gasses stop evolving. Load the reactionmixture directly onto a 25 g ISCO® pre-load column. Dry the column in avacuum oven at room temperature. Purify by eluting through a 40 g ISCO®column with 5% to 20% (2.0 M NH₃ in methanol) in ethyl acetate over 45minutes to give the title compound: TOF MS ES⁺ 319.1 (M+H)⁺, HRMS calcdfor C₁₇H₂₃N₂O₂S 319.1480 (M+H)⁺, found 319.1488, time 0.38 min; HPLC[YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18],t_(R)=10.8 min, 100% purity.

EXAMPLE 115-{4-[(3-Ethylpentylamino)methyl]phenoxy}thiophene-2-carboxamide

Part A: 3-Ethylpentanenitrile

To a suspension of sodium cyanide (3.33 g, 67.8 mmol) in DMSO (24 mL) at60° C., slowly add 1-bromo-2-ethylbutane (10 g, 60.6 mmol). Keep theinternal temperature between 55-60° C. by intermittently cooling with anice bath. Add additional DMSO (10 mL) to keep the slurry stirring. Heatat 70° C. for two hours, then cool to room temperature. Dilute thereaction mixture with water (100 mL) and extract with ether (3×50 mL).Wash the organic extracts with 5.0 N HCl (1×25 mL) and water (1×25 mL).Dry the organic layer over MgSO₄, filter and concentrate to give thetitle compound: ¹H NMR (CDCl₃): 2.34 (d, J=6.2 Hz, 2H), 1.56 (m, 1H),1.46 (m, 4H), 0.93 (t, J=7.3 Hz, 6H).

Part B: 3-Ethylpentylamine

Cool a slurry of LiAlH₄ (4.35 g, 115 mmol) in ether (57 mL) to 0° C.Allow reaction mixture to gently reflux upon the addition of3-ethylpentanenitrile (6.38 g, 57.3 mmol). Stir for two hours beforequenching with 1.0 N NaOH. Filter the suspension through a Celite® pad.Separate the two layers and wash the organic layer with additional 1.0 NNaOH (2×25 mL), dry it over Na₂SO₄, filter and carefully concentrate togive the title compound: ¹H NMR (DMSO-d₆): 2.50 (t, J=7.3 Hz, 2H), 1.24(m, 7H), 0.080 (t, J=7.0 Hz, 6H).

Part C. 5-{4-[(3-Ethylpentylamino)methyl]phenoxy}thiophene-2-carboxamide

Place 5-(4-formylphenoxy)thiophene-2-carboxamide (Example 10, Part C)(0.235 g, 0.948 mmol), 3-ethylpentylamine (Part B) (0.115 g, 0.996 mmol)and 3 Å molecular sieves in a vial. Add methanol (4.7 mL), cap and stirovernight. Add NaBH₄ (0.0359 g, 0.948 mmol) and stir until the gassesstop evolving. Load the reaction mixture directly onto a 25 g ISCO®pre-load column. Dry the column in a vacuum oven at room temperature.Purify by eluting through a 40 g ISCO® column with 5% to 20% (2.0 M NH₃in methanol) in ethyl acetate over 45 minutes to give the titlecompound: TOF MS ES⁺ 347.2 (M+H)⁺, HRMS calcd for C₁₉H₂₇N₂O₂S 347.1793(M+H)⁺, found 347.1799, time 0.38 min; HPLC [YMC-Pro pack C-18 (150×4.6mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0mL/min, 10-20% over 5 min, 20-95% over 18], t_(R)=12.4 min, 100% purity.

EXAMPLE 125-(4-{[2-(Tetrahydropyran-4-yl)ethylamino]methyl}phenoxy)thiophene-2-carboxamide

Place 5-(4-formylphenoxy)thiophene-2-carboxamide (Example 10, Part C)(0.235 g, 0.948 mmol), 2-(tetrahydropyran-4-yl)ethylamine (0.122 g,0.996 mmol) and 3 Å molecular sieves in a vial. Add methanol (4.7 mL),cap and stir overnight. Add NaBH₄ (0.0359 g, 0.948 mmol) and stir untilthe gasses stop evolving. Load the reaction mixture directly onto a 25 gISCO® pre-load column. Dry the column in a vacuum oven at roomtemperature. Purify by eluting through a 40 g ISCO® column with 5% to30% (2.0 M NH₃ in methanol) in ethyl acetate over 45 minutes to give thetitle compound: TOF MS ES⁺ 361.2 (M+H)⁺, HRMS calcd for C₁₉H₂₅N₂O₃S361.1586 (M+H)⁺, found 361.1604, time 0.36 min; HPLC [YMC-Pro pack C-18(150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at1.0 mL/min, 10-20% over 5 min, 20-95% over 18], t_(R)=9.4 min, 100%purity.

EXAMPLE 132-{4-[(3-Methylbutylamino)methyl]phenoxy}thiazole-5-carboxamide

Part A: Ethyl 2-aminothiazole-5-carboxylate

Reference: Plouvier, B.; Bailly, C.; Houssin, F.; Henichart, J. P.Heterocycles, 1991, 32 (4) 693-701.

Dissolve sodium (4.60 g, 200 mmol) in ethanol (100 mL). Cool thesolution to −5° C. to −10° C. and add a mixture of ethyl formate (16.8mL, 220 mmol) and ethyl chloroacetate (27.0 mL, 220 mmol). A whiteprecipitate forms. Add ether (200 mL) to facilitate the precipitation.Warm the reaction mixture to room temperature and stir over night.Filter the precipitate and wash it with ether. Concentrate the filtrateto about ¼ of the volume, add ether (100 mL) and refilter. Dissolve thecombined filter cakes with 10% HCl (100 mL). Extract the acidic aqueousphase with ether (3×100 mL). Dry the organic layer over Na₂SO₄, filterand concentrate. Dilute the liquid with ethanol (106 mL) and addthiourea (8.07 g 106 mmol). Heat the reaction mixture to 80° C. After1.25 hours, concentrate the reaction mixture. Then take the dark oil upin 1.0 N NaOH (100 mL) and extract with dichloromethane (3×100 mL). Drythe organic extracts over Na₂SO₄, filter and concentrate. Suspend thesolid with methanol, then add chloroform. Filter the resultingprecipitate as the title compound: TOF MS ES⁺ 173.0 (M+H)⁺, HRMS calcdfor C₆H₉N₂O₂S 173.0385 (M+H)⁺, found 173.0381, time 0.36 min; HPLC[YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18],t_(R)=6.2 min, 100% purity.

Part B: Ethyl 2-chlorothiazole-5-carboxylate

Reference: Potts, K. T.; Huseby, R. M. J. Org. Chem., 1966, 31,3528-3531.

Dissolve ethyl 2-aminothiazole-5-carboxylate (2.000 g, 11.6 mmol) in 37%HCl (58 mL) at −5° C. Slowly add a solution of sodium nitrite (0.962 g,13.9 mmol) in water (11.6 mL). Maintain a temperature of −5° C. to −10°C. After 2.5 hours, heat the reaction mixture at 50° C. for additional 2hours. Cool the reaction mixture to room temperature, then extract withether (3×100 mL). Wash the organic extract with brine (1×70 mL), dry itover MgSO₄, filter and concentrate. Purify by chromatography elutingwith 10% ether in hexanes to give the title compound: ¹H NMR (CDCl₃):8.14 (s, 1H), 4.36 (q, J=7.0 Hz, 2H), 1.38 (t, J=7.0 Hz, 3H); HPLC[YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18],t_(R)=16.5 min, 100% purity.

Part C: 2-Chlorothiazole-5-carboxamide

Dissolve ethyl 2-chlorothiazole-5-carboxylate (0.927 g, 4.84 mmol) inmethanol. Cool the solution to 0° C., then bubble NH₃ into the reactionmixture for 10 minutes. Then seal the reaction vessel and stir for 3hours. Concentrate the reaction mixture to give the title product: ¹HNMR (CDCl₃): 8.21 (s, 1H), 8.19 (s, 1H), 7.77 (s, 1H); HPLC [YMC-Propack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05%TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], t_(R)=6.9min, 100% purity.

Part D: 2-(4-Formylphenoxy)thiazole-5-carboxamide

Dissolve 2-chlorothiazole-5-carboxamide (0.771 g, 4.78 mmol) and4-hydroxybenzaldehyde (0.584 g, 4.78 mmol) in DMF (15.9 mL). Add K₂CO₃(1.651 g, 11.95 mmol) and heat at 100° C. for 2 hours. Concentrate thereaction mixture. Take the solid up in dichloromethane:methanol (5:1).Add ethyl acetate to precipitate out a white solid. Filter and collectthe solid as the title compound: ¹H NMR (DMSO): 10.00 (s, 1H), 8.11 (s,1H), 8.02 (d, J=8.4 Hz, 2H), 7.94 (s, 1H), 7.59 (d, J=8.8 Hz, 2H), 7.41(s, 1H); HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05%TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min,20-95% over 18], t_(R)=11.4 min, 98.2% purity.

Part E: 2-{4-[(3-Methylbutylamino)methyl]phenoxy}thiazole-5-carboxamide

Place 2-(4-formylphenoxy)thiazole-5-carboxamide (0.187 g, 0.755 mmol),isoamylamine (0.072 g, 0.831 mmol) and 3 Å molecular sieves in a vial.Add methanol (3.8 mL), cap and stir overnight. Add NaBH₄ (0.029 g, 0.755mmol) and stir until the gasses stop evolving. Load the reaction mixturedirectly onto a 25 g ISCO® pre-load column. Dry the column in a vacuumoven at room temperature. Purify by eluting through a 40 g ISCO® columnwith 5% (2.0 M NH₃ in methanol) in ethyl acetate over 45 minutes to givethe title compound: TOF MS ES⁺ 320.1 (M+H)⁺, HRMS calcd for C₁₆H₂₂N₃O₂S320.1432 (M+H)⁺, found 320.1428, time 0.32 min; HPLC [YMC-Pro pack C-18(150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at1.0 mL/min, 10-20% over 5 min. 20-95% over 18], t_(R)=9.7 min, 96.9%purity.

EXAMPLE 142-(4-{[2-(Tetrahydropyran-4-yl)ethylamino]methyl}phenoxy)thiazole-5-carboxamidemethanesulfonate

Place 2-(4-formylphenoxy)thiazole-5-carboxamide (Example 12, Part D)(0.187 g, 0.755 mmol), 2-(tetrahydropyran-4-yl)ethylamine (0.101 g,0.831 mmol) and 3 Å molecular sieves in a vial. Add methanol (3.8 mL),cap and stir overnight. Add NaBH₄ (0.029 g, 0.755 mmol) and stir untilthe gasses stop evolving. Load the reaction mixture directly onto a 25 gISCO® pre-load column. Dry the column in a vacuum oven at roomtemperature. Purify by eluting through a 40 g ISCO® column with 10% (2.0M NH₃ in methanol) in ethyl acetate over 45 minutes to give the titlecompound as a free base. Dissolve the compound indichloromethane:methanol (2:1) (3 mL) and add 1 equivalent of 0.50 Mmethanesulfonic acid in dichloromethane. Stir the solution for a shorttime before concentrating to give the title compound: TOF MS ES⁺ 362.1(M+H)⁺, HRMS calcd for C₁₈H₂₄N₃O₃S 362.1538 (M+H)⁺, found 362.1536, time0.32 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05%TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min,20-95% over 18], t_(R)=8.0 min, 95.0% purity.

EXAMPLE 15 4-{5-[(3-Methyl-butylamino)-methyl]-furan-2-yloxy}-benzamide

Part A: 4-(5-Formyl-tetrahydro-furan-2-yloxy)-benzonitrile

Combine 5-bromo-2-furaldehyde (3.96 g, 32.7 mmol), 4-hydroxybenzaldehyde(1.75 g, 10 mmol), DMF (100 mL), and potassium carbonate (2.07 g, 15mmol), stir, and heat to 120° C. under nitrogen. After 18 hours, cool toambient temperature, partially remove the solvent in vacuo, and dilutewith 300 mL of water. Extract the aqueous solution with ethyl acetate(2×200 mL), wash the organic phase with brine (100 mL). Dry the organicphase over magnesium sulfate, filter, and concentrate under vacuum.Purify via ISCO 100 c system (120 g silica column), using a gradient:80:20 hexane/ethyl acetate to 60:40 hexane/ethyl acetate to give thetitle compound (1.0 g, 46%) as a white solid: ¹H NMR (chloroform-d): 9.5(s, 1H), 7.71 (d, J=9 Hz, 2H), 7.18-7.27 (m, 3H), 5.84 (d, J=4 Hz, 1H).

Part B: 4-(5-Formyl-furan-2-yloxy)-benzamide

Combine 4-(5-Formyl-tetrahydro-furan-2-yloxy)-benzonitrile (1.0 g, 4.69mmol), dimethylsufoxide (100 mL), potassium carbonate (0.32 g, 2.35mmol), and 1 mL of 30% hydrogen peroxide solution. Stir 18 hours atambient temperature. Dilute with 300 mL of ice/water, extract with ethylacetate (3×150 mL). Wash the organic phase with 100 mL of water, and 100mL of brine. Dry the organic phase over sodium sulfate, filter, andconcentrate under vacuum. Purify via ISCO™ 100 c system using a gradientof 75:25 hexane/ethyl acetate to 25:75 hexane/ethyl acetate as elutingsolvent to give 0.18 g (18%) of the title compound: ¹H NMR (DMSO-d₆):9.38 (s, 1H), 7.6 (d, 1H, J=3.8 Hz), 7.30-7.40 (m, 3H), 6.0 (d, 2H,J=3.7 Hz).

Part C:

4-{5-[(3-Methyl-butylamino)-methyl]-furan-2-yloxy}-benzamide

Combine 4-(5-Formyl-furan-2-yloxy)-benzamide (0.18 g, 0.78 mmol),isoamylamine (0.10 g, 0.1.17 mmol), 3 Å molecular sieves (2 g) inmethanol (30 mL), agitate 18 hours at ambient temperature. Add sodiumborohydride (0.058 g, 1.52 mmol), agitate 20 hours at ambienttemperature. Filter through Celite, then concentrate in vacuo. Partitionthe residue between water (50 mL), and ethyl acetate (150 mL). Drain theorganic layer, and dry over sodium sulfate. Purify via ISCO™ 100 c (40 gsilica) using a gradient of 95:5:0.5 to 90:10:1chloroform/ethanol/ammonium hydroxide to afford the title compound(0.160 g, 68%): mass spectrum (ion spray): m/z=303.18 (M+1); HPLCretention time: 5.79 min (HPLC method in this experiment: 5:95-95:5ACN/0.1% TFA in water over 10 minutes using a 15 cm Zorbax column,running at 1 mL/minute, ultraviolet detector set at 254 nM).

1. A compound selected from the group consisting of:4-[5-(Phenethylamino-methyl)-thiophen-2-yloxy]-benzamide

4-{5-[(3-Methyl-butylamino)-methyl]-thiophen-2-yloxy}-benzamide

4-(5-{[2-(3-Fluoro-phenyl)-ethylamino]-methyl}-thiophen-2-yloxy)-benzamide

4-{5-[(2-Cyclopentyl-ethylamino)-methyl]-thiophen-2-yloxy}-benzamide

4-{5-[(2-Thiophen-2-yl-ethylamino)-methyl]-thiophen-2-yloxy}-benzamide

4-{5-[(3,3-Dimethyl-butylamino)-methyl]-thiophen-2-yloxy}-benzamide

3-Methoxy-4-[5-(phenethylamino-methyl)-thiophen-2-yloxy]-benzamide

3-Methoxy-4-{5-[(3-methyl-butylamino)-methyl]-thiophen-2-yloxy}-benzamide

4-[5-(2-Phenethylamino-ethyl)-thiophen-2-yloxy]-benzamide

5-{4-[(3-Ethylpentylamino)methyl]phenoxy}thiophene-2-carboxamide

2-{4-[(3-Methylbutylamino)methyl]phenoxy}thiazole-5-carboxamide

2-(4-{[2-(Tetrahydropyran-4-yl)ethylamino]methyl}phenoxy)thiazole-5-carboxamide

or a pharmaceutically acceptable salt thereof.
 2. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof claim 1 in association with a carrier, diluent and/or excipient.